6FPJ

Structure of the AMPAR GluA3 N-terminal domain bound to phosphate

Summary for 6FPJ

• Entry DOI: 10.2210/pdb6fpj/pdb
• Related: 6FLR
• Descriptor: Glutamate receptor 3, 2-acetamido-2-deoxy-beta-D-glucopyranose, PHOSPHATE ION, ... (6 entities in total)
• Functional Keywords: ligand-gated ion channel, membrane protein, ampa receptor
• Biological source: Rattus norvegicus (Norway Rat)
• Total number of polymer chains: 3
• Total formula weight: 138355.35

Authors

Herguedas, B.,Garcia-Nafria, J.,Greger, I. (deposition date: 2018-02-09, release date: 2018-12-19, Last modification date: 2024-01-17)

Primary citation

Lee, J.Y.,Krieger, J.,Herguedas, B.,Garcia-Nafria, J.,Dutta, A.,Shaikh, S.A.,Greger, I.H.,Bahar, I.
Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.
Structure, 27:241-252.e3, 2019

PubMed Abstract: Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain. Their dysfunction is implicated in many neurological disorders, rendering iGluRs potential drug targets. Here, we performed a systematic analysis of the druggability of two major iGluR subfamilies, using molecular dynamics simulations in the presence of drug-like molecules. We demonstrate the applicability of druggability simulations by faithfully identifying known agonist and modulator sites on AMPA receptors (AMPARs) and NMDA receptors. Simulations produced the expected allosteric changes of the AMPAR ligand-binding domain in response to agonist. We also identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), resulting from its unique conformational flexibility that we explored further with crystal structures trapped in vastly different states. In addition to providing an in-depth analysis into iGluR NTD dynamics, our approach identifies druggable sites and permits the determination of pharmacophoric features toward novel iGluR modulators.

PubMed: 30528594
DOI: 10.1016/j.str.2018.10.017

Experimental method

X-RAY DIFFRACTION (1.96 Å)